Neurotrophic Receptor Tyrosine Kinase (NTRK) Inhibitors and Methods Using Same

A compound selected from the group consisting of:

• (a) a compound of formula (I):
• wherein:
• T is selected from the group consisting of:
• R1 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C6-C10 aryl, optionally substituted C2-C8 heterocyclyl, halogen, C(═O)ORa, C(═O)N(Ra)(Rb), S(═O)2N(Ra)(Rb), CN, and NO2;
• R2 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted phenyl, optionally substituted C2-C8 heterocyclyl, halogen, CN, NO2, ORa, N(Ra)(Rb), C(═O)Ra, C(═O)ORa, OC(═O)Ra, C(═O)N(Ra)(Rb), S(═O)2N(Ra)(Rb), NRaC(═O)Rb, C(═O)N(Ra)(ORb), C(═NRa)N(Rb)(Rc), C(═NRa)N(Rb)(ORc), and NRaS(═O)2Rb;
• R3a, R3b, R3c, R3d, and R3e are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, halogen, CN, and NO2;
• R4 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, C(═O)(optionally substituted C1-C6 alkyl), optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 aminoalkyl, optionally substituted C2-C6 hydroxyalkyl, optionally substituted benzyl, and optionally substituted phenyl;
• R5 is selected from the group consisting of H and —X1-A1;
• R6a, R6b, R6c, and R6d are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, and C(═O)N(Ra)(Rb);
• L1 is —C(R6a)(R6b)—;
• L2 is selected from the group consisting of a bond, —C(═O)—, —C(═O)(optionally substituted C1-C3 alkylenyl), —C(═O)(optionally substituted C2-C3 alkenylenyl), —C(═S)—, —C(═S)(optionally substituted C1-C3 alkylenyl), —C(═S)(optionally substituted C2-C3 alkenylenyl), —S(═O)2—, —S(═O)2(optionally substituted C1-C3 alkylenyl), —S(═O)2(optionally substituted C2-C3 alkenylenyl), optionally substituted C1-C3 alkylenyl, and optionally substituted C2-C3 alkenylenyl;
• X1 is selected from the group consisting of a bond, O, and NR7;
• R7 is selected from the group consisting of H and optionally substituted C1-C6 alkyl;
• A1 is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted C2-C8 heterocyclyl;
• Ra, Rb, and Rc are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted C2-C8 heterocyclyl;
• and
• wherein, if
• is and -L2-R5 is —H, then R4 is not H;
• or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixtures thereof;
• (b) a compound of formula (II):
• wherein:
• A2 is selected from the group consisting of:
• R8 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted phenyl;
• R9a, R9b, R9c, and R9d are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C6-C10 aryl, optionally substituted C2-C8 heterocyclyl, halogen, CN, and NO2;
• R10 is selected from the group consisting of optionally substituted C1-C6 alkyl,
• R11a, R11b, R11c, R11d, R11e, R11f, R11g and R11h are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted phenyl, optionally substituted C2-C8 heterocyclyl, halogen, CN, NO2, ORa, N(Ra)(Rb), C(═O)Ra, C(═O)ORa, OC(═O)Ra, C(═O)N(Ra)(Rb), S(═O)2N(Ra)(Rb), NRaC(═O)Rb, and NRaS(═O)2Rb;
• R12a, R12b, and R12c are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted benzyl, and optionally substituted phenyl;
• R13a, R13b, R13c, and R13d are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, halogen, CN, and NO2;
• R14 is selected from the group consisting of H and optionally substituted C1-C6 alkyl;
• L3 is selected from the group consisting of:
• X2 is selected from the group consisting of O and NR14;
• Z1 is selected from the group consisting of CR13a and N, Z2 is selected from the group consisting of CR13b and N, Z3 is selected from the group consisting of CR13c and N, and Z4 is selected from the group consisting of CR13d and N,
• wherein at least one selected from the group consisting of Z1, Z2, Z3, and Z4 are N;
• and
• Ra and Rb are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted C2-C8 heterocyclyl;
• or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixtures thereof, and
• (c) a compound of formula (III):
• wherein:
• R15a, R15b, and R15c are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, halogen, CN, and NO2;
• R16 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted benzyl, and optionally substituted phenyl;
• R17a and R17b are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted benzyl, and optionally substituted phenyl;
• R18a and R18b are each independently selected from the group consisting of H and optionally substituted C1-C6 alkyl;
• A3 is optionally substituted phenyl;
• and
• A4 is optionally substituted phenyl;
• or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixtures thereof.